The eye possesses a unique physiological adaptation that modifies the induction and expression of immunity within its tissues. This physiological adaptation is known as immune privilege. Normally the eye is an immune privileged site. The physiological role of immune privilege appears to be a mechanism by which the eye receives immune protection but avoids the destructive side-effects of immunogenic inflammation. Immunogenic inflammation associated with delayed hypersensitivity reactions can grossly distort the visual axis resulting in blindness. Consequently, immune protection within the eye involves a selective deficiency of T-cells that mediate delayed hypersensitivity. To control immunogenic inflammation, the cells and neurons within the ocular microenvironment produce immunomodulating factors that actively suppress T-cell inflammatory-mediating activities. Biochemical examination of aqueous human has revealed the identity of some of the immunomodulating factors. They are the neuropeptides alpha-melanocyte stimulating hormone (alpha- MSH), and vasoactive intestinal peptide (VIP), along with transforming growth factor-beta (TGF-beta). To demonstrate the activity of the neuropeptides with TGF-beta in the eye, the effects of normal aqueous humor. which contains the immunoregulatory cytokines produced in the eye, on effector T-cell activities will be examined. Primed T-cells treated with normal aqueous humor, neuropeptide depleted aqueous humor, or neuropeptides alone will be examined for the production of cytokines (secreted protein and mRNA expression) following antigen stimulation. The expectation is that when the neuropeptides are present in aqueous human T- cell inflammatory activity (production of IFN-gamma and TNFalpha) will be suppressed. To define the role of the neuropeptides in vivo, the inability of the eye to prevent immune-mediated inflammation will be examined in eyes that have been chemically denervated. The expectation is that such eyes can no longer prevent the induction of immune inflammation and therefore have lost an important part of ocular immune privilege. The results of this project will imply that immunomodulation in the eye involves a neurological component . Understanding thr activity of intraocular immunomodulatory factors will make it possible to manipulate the intraocular microenvironment in a manner that promotes immune elimination of pathogens and tumors without the binding consequence of immunogenic inflammation, to prevent or cure autoimmune ocular diseases, and to promote the success of ocular transplants of corneal and retinal cells and tissues.